The overall objective of the proposed study is to investigate the hypothesis that the regulatory events which control the immune response to a complex globular protein involves the recognition of different determinants by distinct subpopulations of lymphocytes with antagonistic regulatory function in a process influenced by the expression of the major histocompatibility complex (MHC). In that light, it is the general aim of this proposal to identify the cellular and genetic mechanisms which operate in the regulation of the response to individual determinants in order to more fully comprehend how their interplay leads to the phenotypic pattern of the response to the whole antigen. To address these questions, the antigen-induced T cell proliferative response will be analyzed using the well-defined globular protein antigen, cytochrome c. The possibility will be tested that certain antigenic determinants on the cytochrome c molecule selectively activate T suppressor cells, whereas others preferentially stimulate proliferating T cells. Moreover, we will ask whether there exist additional subsets of T cells within this proliferating population specific for cytochrome c which are under separate Ir gene control and which must cooperate with one another in order to obtain an optimal proliferative response to cytochrome c. Finally the apparent ease with which it is possible to demonstrate suppression in this system, makes cytochrome c an ideal probe to study the possible role of thymus H-2 in controlling T suppressor cells. These issues will be investigated using T cells obtained by conventional methods as well as by recently developed techniques permitting one to specifically enrich antigen-specific T cells by in vitro cultivation and by the fusion of such propagated cells with T cell tumor lines to yield functional, antigen-inducible T cell hybridomas. The delineation of the mechanism by which the immune system is regulated under normal conditions may provide insights into how perturbation of such regulation may lead to certain pathologic states. Furthermore, such information may also permit the immune system to be specifically manipulated in clinical settings: enhanced in the case of immunity to infectious agents or neoplasms, or suppressed in the case of transplantation.